1. Asthma and Pregnancy Michael Schatz, MD, MS Chief, Department of Allergy Kaiser-Permanente Medical Center San Diego, CA

2. Disclosures Investigator-initiated Research Support –Aerocrine –Genentech –GlaxoSmithKline –Merck Research Consultant –Amgen –GlaxoSmithKline –Merck

3. Asthma and Pregnancy Most common potentially serious medical problem to complicate pregnancy May increase the risk of perinatal complications The risks of uncontrolled asthma appear to be greater than the risks of asthma medications Aggressive asthma management similar to non- pregnant patients is recommended

4. Asthma and Pregnancy: Clinically Relevant Questions Does asthma control make a difference? Are asthma medications safe during pregnancy? What are the barriers to asthma control during pregnancy? What is the role of exhaled nitric oxide in asthma management during pregnancy?

5. Relationship to Asthma Control Case reports—severe exacerbations associated with Maternal and/or fetal deaths Severe infant neurologic disease Studies Parameters of asthma control Symptoms FEV 1 Exacerbations Outcomes affected Low birth weight/SGA Preterm birth Congenital malformations (one study).

6. Asthma Symptom Control and Preterm Birth Controlled = symptoms not interfering with sleep or activity Multivariate analysis adjusted for: –Age –BMI –Parity –SES –Smoking –Race/ethnicity –Oral corticosteroids 719 WomenUnivariate: Incidence (%) of Preterm Birth) Multivariate: Odds ratio (95 % CI) Controlled (56.3 %) 6.3Reference Uncontrolled (43.7 %) 11.41.83 (1.04-3.25) Bakhireva. Ann Allergy Asthma Immunol 2008; 101:137

7. Relationship Between FEV 1 During Pregnancy and Prematurity OutcomeMean FEV 1 < 80 % (n = 354) Mean FEV 1  80 % (n = 1769) Preterm < 32 weeks 5.1 %3.0 % Preterm < 37 weeks 21.2 %15.3 % Low birth weight 17.6 %12.9 % Schatz.. Am J Obstet Gynecol 2006; 194:120

8. The Relationship of Asthma Exacerbations During Pregnancy to Infant Low Birth Weight Murphy. Thorax 2006; 61:169

9. Asthma Severity/Control and Congenital Malformations Canadian administrative database study 4344 pregnancies of asthmatic women Incidence of malformations –9.2 % total –6.0 % major Odd Ratio (95 % CI) for patients with first trimester exacerbations –Total 1.48 (1.04-2.09) –Major 1.32 (0.86-2.04) Blais. J Allergy Clin Immunol 2008; 121:1379

10. Conclusions Regarding Asthma Control Better control (based on symptoms, pulmonary function, exacerbations) associated with improved outcomes –LBW –Preterm –SGA –Congenital malformations Relationship can’t be proven by RCTs (random assignment to controlled versus not controlled )

11. Asthma and Pregnancy: Clinically Relevant Questions Does asthma control make a difference? Are asthma medications safe during pregnancy? What are the barriers to asthma control during pregnancy? What is the role of exhaled nitric oxide in asthma management?

12. Asthma Medications and Prematurity/Fetal Growth StudySABAICSOral CS Number exposed Schatz, 1997 (Kaiser) 488*149*130 (↑ pre-eclampsia) Bracken, 2003 (Yale) 529*176*52 (↑ preterm) Schatz, 2004 (MFMU) 1753*722*185 (↑ preterm and LBW) * No increased risk

13. Congenital Malformations Total malformations –Background risk of 3-5 % Increased risk of specific malformations –Drugs are generally associated with an increased risk of specific, rather than total malformations –Most studies have inadequate power for specific malformations –Confounding by control/severity still possible

14. Specific Congenital Malformations and Bronchodilators Albuterol or bronchodilators (primarily albuterol) –Cardiac –Gastroschisis –Cleft lip/palate LABA –Cardiac Kallen, 2007; Lin, 2008; Lin, 2009; Munsie, 2011; Eltonsy, 2011

15. Congenital Malformations and Corticosteroids Inhaled –No significant increase in Swedish Medical Birth Registry study 11,487 total 10,013 budesonide –Increased total malformations in high dose users versus other users in one database study Oral –Increased oral clefts in case control studies –Not confirmed in recent cohort study Kallen, 2007; Blais, 2009; Park-Wylie, 2000 ; Hvid, 2011

16. Asthma Medications: Conclusions Asthma medications (other than prednisone) not likely to be the cause of prematurity or reduced fetal growth Bronchodilators, oral corticosteroids, and possibly high dose inhaled corticosteroids have been associated with certain birth defects Confounding by indication (more severe disease and exacerbations) may explain these associations

17. Asthma and Pregnancy: Clinically Relevant Questions Does asthma control make a difference? Are asthma medications safe during pregnancy? What are the barriers to asthma control during pregnancy? What is the role of exhaled nitric oxide in asthma management?

18. Barriers to Asthma Control Smoking –Associated with increased exacerbations Clinician undertreatment –Documented in ED Adherence –Substantial proportion of women reduce medications –Common cause of exacerbations Viral infections –Most common cause of exacerbations Murphy, 2010; Cydulka, 1999; McCallister, 2011; Enriquez, 2006; Murphy, 2005

19. Asthma and Pregnancy: Clinically Relevant Questions Does asthma control make a difference? Are asthma medications safe during pregnancy? What are the barriers to asthma control during pregnancy? What is the role of exhaled nitric oxide in asthma management?

20. Exhaled Nitric Oxide (eNO) and Pregnancy Mean levels of eNO were not different in asthmatic pregnant versus non-pregnant women Mean ACT scores were not different in asthmatic pregnant versus non-pregnant women Levels of eNO were modestly (r = 0.30) but significantly (p = 0.02) correlated with ACT scores in pregnant asthmatic women Tamasi. J Asthma 2009; 46:786

21. Managing Asthma in Pregnancy (MAP) Study Double blind parallel group RCT 220 pregnant asthmatic women Algorithm based on eNO and ACQ –Inhaled corticosteroid increased with inadequate control and high eNO –Formoterol increased with inadequate control and low eNO –Inhaled corticosteroid decreased with adequate control and low eNO Powell. Lancet 2011; 378:983

22. Incidence of Exacerbations Over Time

23. Comparison of Treatment Profiles

24. Comparison of ICS Doses 123 4 56 500 600 700 800 900 Control group FENO group p=0.043 Visit Mean ICS Dose (ug/day)

25. Conclusions Asthma control during pregnancy makes a difference Asthma medications appear to have few risks during pregnancy, and those risks that have been identified may be due to confounding There are barriers that need to be addressed to improve asthma control during pregnancy eNO may allow more targeted and more effective management of asthma during pregnancy